This invention concerns the treatment of two major types of movement disorders 1) tardive dyskinesia (TD), tardive dystonia and related movement disorders, induced by exposure to neuroleptic (antipsychotic) drugs; 2) focal dystonias not related to medications, including blepharospasm, Meige syndrome, torticollis, spasmodic dysphonia, and writer's cramp; and 3) tics, including multiple tics and Gilles de la Tourette syndrome (TS).
Movement disorders affect a significant portion of the population, causing disability as well as distress. Tardive dyskinesia (TD) is a chronic disorder of the nervous system, characterized by involuntary, irregular rhythmic movements of the mouth, tongue, and facial muscles. The upper extremities also can be involved. These movements may be accompanied, to a variable extent, by other involuntary movements and movement disorders. These include rocking, writhing, or twisting movements of the trunk (tardive dystonia), forcible eye closure (tardive blepharospasm), an irresistible impulse to move continually (tardive akathisia), jerking movements of the neck (tardive spasmodic torticollis), and disrupted respiratory movements (respiratory dyskinesia). The vast majority of TD cases are caused by the prolonged use of antipsychotic drugs (neuroleptics). A relatively small number are caused by the use of other medications, such as metoclopramide, that, like neuroleptics, block dopamine receptors. TD often manifests or worsens in severity after neuroleptic drug therapy is discontinued. Resumption of neuroleptic therapy will temporarily suppress the involuntary movements, but may aggravate them in the long run.
TD is also associated with a variable degree of cognitive impairment. Cognitive dysfunction associated with TD may involve attention, concentration, memory, or executive functions such as judgment or abstract reasoning. (see, e.g., Sachdev et al., Acta Psychiatr Scand 93:451, 1996; Waddington & Youssef, Psychol. Med. 26:681, 1996; Swartz, Neuropsychobiology 32:115, 1995). The cognitive impairment associated with TD usually is seen as a marker of underlying differences in brain function that predispose the patient to TD. However, it may also be due to the TD itself, and may be either irreversible, or partially reversible if the TD is successfully treated.
Tardive dyskinesia (TD) affects approximately 15-20% of patients treated with neuroleptic drugs (Khot et al., Neuroleptics and Classic Tardive Dyskinesia, in Lang A E, Weiner W J (eds.): Drug Induced Movement Disorders, Futura Publishing Co., 1992, p. 121-166). Neuroleptics are used to treat several common psychiatric disorders, including schizophrenia and related psychoses (estimated prevalence 1%), mood disorders with psychotic features (estimated minimum prevalence 0.5%), and Alzheimer's disease with psychosis or agitation (estimated minimum prevalence at 0.5%. Assuming that half of those in need of neuroleptic treatment receive it, it follows that TD affects hundreds of thousands of people in the United States alone. The cumulative incidence of TD is substantially higher in women, in older people, and in those being treated with neuroleptics for conditions other than schizophrenia, such as bipolar disorder (manic-depressive illness) (see, e.g., Hayashi et al., Clin. Neuropharmacol, 19:390, 1996; Jeste et al., Arch. Gen. Psychiatry, 52:756, 1995). Unlike the acute motor side effects of neuroleptic drugs, TD does not respond in general to antiparkinson drugs (Decker et al., New Eng. J. Med., Oct. 7, p. 861, 1971).
The focal dystonias are a group of movement disorders involving the intermittent sustained contraction specific muscle groups, resulting in recurrent abnormal posturing of some part of the body. The most common is spasmodic torticollis, which involves twisting of the neck. Other examples are blepharospasm, which involves involuntary eye closure or excessively forceful blinking, and writer's cramp, which involves contraction of the muscles of the hand. Another less common focal dystonias involve the laryngeal muscles (spasmodic dysphonia). Other relatively rare dystonias involve muscle groups specific to a particular occupation, such as playing the violin. The prevalence of focal dystonias in one US county was estimated as 287 per million (Monroe County Study); this suggests that at least 70,000 people are affected in the US alone. Blepharospasm alone affects more than 25,000 people (Source: US FDA Web Site; page on Orphan Drug Act).
Tics are estimated to affect 1% to 13% of boys and 1% to 11% of girls, the male-female ratio being less than 2 to 1. Approximately 5% of children between the ages of 7 and 11 years are affected with tic behavior (Leckman et al., Neuropsychiatry of the Bas. Gang, December, 20(4): 839-861, 1997). The estimated prevalence of multiple tics with vocalization, i.e. Tourette's syndrome, varies among different reports, ranging from 5 per 10,000 to 5 per 1,000. Tourette's syndrome is 3-4 times more common in boys than girls and 10 times more common in children and adolescents than in adults (Leckman et al., supra; Esper et al, Tenn. Med., January, 90:18-20, 1997).
A tic is an abrupt repetitive movement, gesture, or utterance that often mimics a normal type of behavior. Motor tics include movements such as eye blinking, head jerks or shoulder shrugs, but can vary to more complex purposive appearing behaviors such as facial expressions of emotion or meaningful gestures of the arms and head. In extreme cases, the movement can be obscene (copropraxia) or self injurious. Phonic or vocal tics range from throat clearing sounds to complex vocalizations and speech, sometimes with coprolalia (obscene speech) (Leckman et al., supra). Tics are irregular in time, though consistent regarding the muscle groups involved. Characteristically, they can be suppressed for a short time by voluntary effort.
Gilles de la Tourette syndrome (TS) is the most severe tic disorder. Patients with TS have multiple tics, including at least one vocal (phonic) tic. TS becomes apparent in early childhood with the presentation of simple motor tics, for example, eye blinking or head jerks. Initially, tics may come and go, but in time tics become persistent and severe and begin to have adverse effects on the child and the child's family. Phonic tics present, on average, 1 to 2 years after the onset of motor tics. By the age of 10, most children have developed an awareness of the premonitory urges that frequently precede a tic. Such premonitions may enable the individual to voluntary suppress the tic, yet premonition unfortunately adds to the discomfort associated with having the disorder. By late adolescence/early adulthood tic disorders can improve significantly in certain individuals. However, adults who continue to suffer from tics often have particularly severe and debilitating symptoms. (Leckman et al., supra).
The pathophysiology of movement disorders, specifically TD, TD has not been established definitively. It is well known that blockade of dopamine receptors will lead to an increased number of dopamine receptors, and therefore to an increased sensitivity to dopamine of striatal neurons. (see e.g., Andrews, Can J Psych 39:576, 1994; Casey, in Psychopharmacology: The Fourth Generation of Progress, Raven Press, 1995). The first major hypothesis about the pathophysiology of TD was that TD was the result of this hypersensitivity of striatal neurons to dopamine. In support of the "dopamine supersensitivity" hypothesis, it is noted that dopamine agonists can aggravate the disorder (Bezchibnyk-Butler & Remington, Can J. Psych,. 39:74, 1994). However, the dopamine supersensitivity hypothesis is not compatible with the observation that TD and Parkinsonism (a dopamine deficiency state) often exist together in the same patient.
Other studies have suggested that irreversible cases of TD may be related to excitotoxic damage to the basal ganglia (Andreassen & Jorgensen, Pharmacol. Biochem. Behav., 49(2):309-312, 1994; Tsai et al.,: Am J Psych, September 155:9, 1207-13, 1998). An acquired deficiency of the inhibitory neurotransmitter GABA has also been implicated in the development of TD.
A widely-studied animal mode of TD, that of vacuous chewing movements (VCM) in rats, has also yielded evidence for a glutamate-based excitotoxic mechanism in the development of the disorder (Meshul et al; Psychopharmacology (Berl), 125:238-47, 1996 June; Andreassen et al; Br J Pharmacol, 199:751-7, 1996 October) When administered to rats with VCM, ethanol acutely decreases the animal's orofacial movements. This effect is prevented if the rats are pre-treated with a benzodiazepine inverse agonist, suggesting that it is mediated by stimulation of GABA-A receptors by ethanol (Stoessl, Pharmacol. Biochem. Behav. July, 54:541-6, 1996 July) Stoessl suggests that "GABAergic stimulation" deserves further investigation in the treatment of TD. He does not, however, advance the idea of treating TD with NMDA antagonists, nor suggest using memantine as a treatment for TD.
The physical manifestations of TD can resemble movement disorders associated with degenerative diseases such as Huntington's disease and Parkinson's disease. Patients with TD can show chorea (quick, irregular movements of the extremities) indistinguishable from that seen in cases of Huntington's disease. Neck, trunk and limb movements of TD can be indistinguishable from those of the peak-dose dyskinesia associated with prolonged treatment of Parkinsons disease with levodopa. The physical manifestations of tardive dystonia are nearly identical to the manifestations of the idiopathic dystonias, i.e., those not related to exposure to dopamine antagonists. (See the further discussion below.)
It is evident that similar mechanisms may be involved in the pathophysiology of tardive movement disorders and idiopathic focal dystonias. Positron emission tomography has shown that one specific dystonia, torticollis, is associated with neuronal hypermetabolism in the basal at ganglia. It has been hypothesized that hyperactivity of a motor control loop involving the cerebral cortex, basal ganglia, and thalamus is responsible for the abnormal postures and movements (i.e. movements into and out of abnormal postures) characteristic of dystonia (Galardi et al., Acta. Neurol Scand, September, 94:172-6, 1996). Other studies have shown abnormal dopaminergic transmission or receptor function in patients with dystonia (see, e.g. Perlmutter et al., J Neurosci, Jan. 15, 17:843-50, 1997). Of note, both too much or too little dopamine may be associated with dystonia, since patients with Parkinson's disease and dystonia can have the problem both at peak and trough levels of levodopa (Hallett, Arch. Neurol. May, 55:601-3, 1998). Although memantine has dopamine agonist activity, memantine has not been suggested as a treatment for focal dystonias.
The pathophysiology of tic disorders like, that of TD, has not yet been established difinitively, although several plausible hypotheses have been set forth. The pathophysiology of tic disorder resembles the mechanism that may be involved in the pathophysiology of tic disorders and focal dystonias. Excessive activity of a cortical-striatal-pallidal-thalamic-cortical sensorimotor loop has been implicated in the lack of motor impulse control associated with tic disorders (Zambian et al., Am. J. Psychiatry, Vol 154, September, 1997; Leckman et al., supra). This hyperactivity may reflect excessive dopaminergic activity in the striatum, or a relative deficiency of inhibitory transmission. While dysfunction of the basal ganglia or their connections is likely to be present, the basal ganglia, thalamus, and motor cortex are anatomically normal in most cases.
Treatment of TD
Recent research suggests that Vitamin E can reduce symptoms of TD modestly (Lohr & Caliguiri, J Clin Psychiatry 57; 167, 1996; Dabiri et al. Am. J. Psychiatry, June, 151(6):925-926, 1994). GABA agonists such as baclofen and various benzodiazepines have also been the subject of some positive reports and are widely used in practice to ameliorate the symptoms of TD, probably because their low toxicity justifies their use despite their limited efficacy. (Gardos & Cole, Psychopharmacology: The Fourth Generation of Progress, eds. Bloom and Kupfer, pp. 1503-1510, 1995). The latter review cited reports of variable benefits associated with other agents including propranolol, clonidine, cholinergic agonists, buspirone and calcium-channel antagonists. However, none of these has become a generally accepted treatment for either the movement or cognitive disorders associated with TD. (The author has had some success in treating TD with nimodipine, a calcium-channel antagonist with particularly good penetration of the CNS.)
In U.S. Pat. No. 5,602,150, by Lidsky et al., it was proposed that the emergence of TD in patients receiving neuroleptics might be prevented by simultaneously administering taurine or taurine derivatives. Lidsky based his invention on the theory that TD is due to excitotoxic damage, and that taurine and taurine derivatives would protect patients against this damage. The recommendation of taurine is based on studies in a single animal model. The experiments reported do not deal with any therapeutic effects of taurine on established movements, either in the presence of continued neuroleptic administration or otherwise. Neither the patent nor the experiments cited in it predict or imply that taurine or derivatives will be beneficial for established movement disorders. Moreover, the mechanism proposed by Lidsky et al., (supra) is based on long-term neuroprotection. He neither infers, asserts, suggests nor suggests that taurine or taurine derivatives might have any immediate, short-term effect on movement disorders.
Memantine is a drug approved in Europe for treatment of Parkinson's disease. Memantine, a congener of amantadine, is a N-methyl-D-aspartate type glutamate receptor blocker ("NMDA receptor antagonist" or "NMDA receptor blocker") as well as a dopamine agonist. Although memantine has been reported to alleviate some of the dyskinetic movements that can be seen in treated Parkinson's disease, there are no reports of its use in humans to treat tardive dyskinesia, and at least one widely-reputed expert in the field of TD expressed surprise that any anti-Parkinson's drug would be an effective agent against TD (Dilip Jeste, M. D., personal communication, 1997).
In U.S. Pat. No. 4,122,193, it is reported that 1,3,5-trisubstituted adamantane, including 1-amino-3,5-dimethyl-adamantane is useful in the treatment of hyperkinesis in rats. The agent is also recommended as a treatment generally for hyperkinesis, in the context of Parkinson's disease, head tremors, thalamic tension conditions, and spastic conditions, and for "the activation of patients with akinetic cerebroorganic conditions". It is notable that, unlike TD, none of the underlying conditions described in that patent as the context of the hyperkinesis to be treated, is thought to be aggravated by dopamine agonists. Moreover, there is no recognition in the reference that 1-amino-3,5-dimethyl-adamantane acts as a NMDA-receptor blocker. Instead, the disclosure indicates that 1,3,5-trisubstituted adamantane compounds influence catecholamine metabolism, for instance by freeing dopamine or stimulating the receptors. This latter aspect suggests that the authors did not recognize that memantine could be an effective treatment of TD, for which administration of dopamine agonists in general goes against expert opinion.
In co-pending, commonly-owned applications Ser. Nos., 08/861,801 and 09/006,641, incorporated herein by reference, treatments with memantine (a congener of amantadine and a N-methyl-D-aspartate type (NMDA) receptor blocker as well as a dopamine agonist), and acamprosate (a calcium salt of a derivative of the amino acid taurine and an indirect NMDA antagonist and GABA-A agonist), were advanced as effective treatments for both the movement and the cognitive disorders associated with TD, and were reported to be dramatically effective in several severely affected individuals. The cases described in those patent applications contain the first reports of the use of memantine for the treatment of TD.
Treatment of Focal Dystonia
As noted above, a focal dystonia is a movement disorder involving recurrent abnormal posturing of some part of the body. The spasms of focal dystonia can last many seconds at a time, causing major disruption of the function of the affected area. No systemic drug therapy is generally effective, but some drugs give partial relief to some patients. Those most often prescribed are anticholinergics, baclofen, benzodiazepines, and dopamine agonists and antagonists. The most consistently effective treatment is the injection of botulinum toxin into affected muscles.
The various focal dystonias tend to respond to the same drugs (i.e., treatments that are helpful for one focal dystonia generally have been helpful for others.) (Chen, Clin. Orthop, June, 102-6, 1998; Esper et al; Tenn. Med, January, 90:18-20, 1997; De Mattos et al., Arq. Neuropsychiatry, March 54:30-6, 1996). Published clinical experience to date suggests that a new treatment that reduced the involuntary movements of one focal dystonia would be likely to do the same for the involuntary movements of another. Furthermore, the common symptoms, signs, and responses to medication of spontaneous (idiopathic) dystonia and neuroleptic-induced dystonia suggest that an effective treatment for a drug-induced focal dystonia will be effective for the same dystonia occurring spontaneously.
Blepharospasm, one of the focal dystonias, is a condition that involves continually recurring involuntary eye closure or excessive forceful blinking. Blepharospasm is one of the most common disorders of oculomotor function. It is variably regarded as a facial dyskinesia or a facial dystonia. When it occurs together with dystonia of the oral and mandibular regions, with or without involvement of the neck, it is referred to as Meige syndrome. Blepharospasm can significantly impair visual function. Patients can become unable to read, to drive an automobile, or to do any skilled work requiring visual control. Blepharospasm can occur spontaneously (idiopathic blepharospasm) and with a prevalence that increases with increasing age; most cases arise in the fifth and sixth decades of life (Holds et al., Am. Fam. Physician, June, 43:2113-20, 1991). It also can occur as a sequel to neuroleptic drug treatment (Ananth et al., Am. J. Psychiatry, April, 145:513-5, 1988; Kurata et al., Jpn. J. Psychiatry. Neurol., December, 43:627-31, 1989; Sachdev et al., Med. J. Aust., Mar. 20, 150:341-3, 1989) and perhaps treatment with other classes of psychotropic drugs (Mauriello et al., J Neuropathol, June, 18:153-7, 1998), either alone or in conjunction with tardive dyskinesia or other forms of tardive dystonia. Another report of 19 patients with severe tardive dyskinesia, stated that frequent eye blinking was the most frequent prodromal sign of the disorder (Gardos et al., supra, 1988). The oculomotor phenomena of idiopathic blepharospasm and Meige syndrome are identical with those seen in cases induced by neuroleptic treatment. Differences between idiopathic blepharospasm and tardive blepharospasm do not involve the ocular movements themselves. (Observed differences have involved family history and the likelihood that other non-ocular involuntary movements will be present.)
Though many substances have been tested for their ability to relieve blepharospasm, injection of botulinum toxin into orbicularis oculi muscles is the mainstay of treatment (Mauriello et al., Br. J. Ophthalmol, December, 80:1073-6, 1996). These injections weaken the muscles responsible for eye closure, thereby mitigating the involuntary movements of those muscles. They may also indirectly influence oculomotor control by the central nervous system, by altering the input from motor nerve afferents. Botulinum toxin injections have become treatment of choice because they ameliorate symptoms in approximately 80% of patients--a much greater proportion than benefit from the numerous systemic drug treatments tried to date.
Movements associated with blepharospasm do not respond well to the systemic drug treatments employed to date. In one large case series, only 22% of blepharospasm patients treated with systemic medications got marked and persistent relief (Jankovic et al., Mov. Disord., May, 9:347-349,1983). In another report, of the 13 patients with blepharospasm who did not do well with botulinum toxin injections, only 2 showed any improvement when given systemic drug therapy (Mauriello et al., Clin. Neurol. Neurosurg., August, 98:213-6, 1996)). Even botulinum toxin injections are not always efficacious. Surgery is sometimes recommended for patients who do not get relief from botulinum toxin injections (Elston et al., J. Neurol, January, 239:5-8, 1992).
Of the numerous systemic treatments tried for the treatment of blepharospasm, (see, for example, Arthurs et al., Can. J. Ophthalmol; February, 22:24-8, 1987; Casey et al., Neurology, July, 30:690-5, 1980; Jacoby et al., Invest. Ophthalmol. Vis. Sci., March, 31:569-76, 1990; Michaeli et al., Clin. Neuropharmacol., June, 11:241-9, 1988; Ransmayr et al., Clin. Neuropharmacol., February, 11:68-76, 1988) clonazepam, a GABA agonist, was the only drug consistently found useful (Jankovic et al., Ann. Neurol., April, 13:402-11, 1983). A combination of two GABA agonist agents, valproate and baclofen, was efficacious in a single case (Sandyk, et al., S Afr Med J, December, 64:955-6, 1983). Tetrabenazine, a dopamine depleting agent, alleviated involuntary movements in 4 of 6 patients with Meige syndrome, but the patients had many undesirable side effects including drowsiness, drooling and Parkinsonism (Jankovic, et al., Ann Neurol, January, 11:41-7, 1982). Because of such unpleasant side effects, tetrabenazine has not become a widely-used treatment for blepharospasm, tics or even tardive dyskinesia, despite the absence of other generally effective treatments for these conditions. Neuroleptics sometimes relieve symptoms of blepharospasm, but they do so less well than tetrabenazine, and patients treated with them run the risk of developing TD or other tardive movement disorders. In sum, though drugs that reduce dopaminergic transmission have been employed with some benefit in the treatment of idiopathic blepharospasm, neither type of medication has proved to be a generally satisfactory treatment.
Treatment of Tics and Tourette's Syndrome
Patients with moderate to severe motor and vocal tics are likely to require drug therapy. Many classes of neurological and psychiatric medications have been tried, but only neuroleptics, alpha-2 adrenergic agonists, and clonazepam have attained the status of standard treatments. (For recent reviews see Chappell et al., Neur. Clin. of North Am., 15(2), May 1997; Kurlan, Neurol. Clin., May, 15:403-409, 1997; Lichter et al., J. Child Neur., 11(2), March, 1996; Leckman et al., supra; Esper et al, Tenn. Med., January, 90:18-20, 1997; Scahill et al., J. Child Adolesc Phychopharcmacol, 7(2), 1997; incorporated herein by reference). Unfortunately, all three of the commonly-used treatment for TS have significant drawbacks.
The most common therapies used for the treatment of tic disorders are the neuroleptics (i.e. dopamine antagonist antipsychotic drugs). Within this category, haloperidol and pimozide are most often used in the United States. Neuroleptic treatment usually will suppress the involuntary movements of tic disorders, with up to 85% of patients experiencing relief--Esper et al., supra). The side effects of neuroleptic drugs include sedation, depression, parkinsonism, cognitive impairment, and tardive dyskinesia. Other tardive movement disorders can develop with prolonged use. The intolerability of side effects often leads patients to discontinue neuroleptic therapy for TS, while the risk of TD makes most physicians unwilling to use them in milder cases. Those with more severe TS must often make an unpleasant choice between distressing symptoms and distressing side effects. People with simple tics may experience emotional distress, embarrassment, impaired self-esteem, or physical injury if their tics are sufficiently violent. Yet, they usually will not be treated with neuroleptics because their side effects and long-term toxicity that are not acceptable in the treatment of relatively mild cases.
Other drug treatments for TS do not carry the risk of TD. But they are less efficacious than neuroleptics. The most common non-neuroleptic alternatives are alpha-2 adrenergic agonists such as clonidine. Unfortunately, fewer than 50% (perhaps as few as 25%) of patients treated with clonidine show clinically significant improvement of tic-related symptoms (Esper et al., supra; Chappell et al., supra). Further, many patients whose tics do respond to clonidine will have side effects that limit its use, most often hypotension or sedation.
Another non-neuroleptic treatment, clonazepam, a benzodiazepine with GABA-A and serotonergic actions, has some efficacy in the treatment of Tourette's syndrome (Steingard et al., J. Am Acad Child Adolesc Psychiatry, March-April, 33:394-9, 1994). Sedation and ataxia limit the dosage of clonazepam; the tolerable dose often is below that needed to suppress the patient's tics.
A new class of compounds that act as antagonists of brain serotonergic 5-HT.sub.2 receptors initially showed promising results, although children and adolescents experience increase in sensitivity to side effects. (Chappell et al., supra). Additional alternatives that have received recent attention include antioxidant treatment (Rotrosen et al., Prost. Leuk. and Ess. Fatty Acids, 55(1 & 2), 1996), transcranial magnetic stimulation (Ziemann et al., supra), nicotine treatment (Sanberg et al., Phamacol. Ther., 74(1)., 1997; Silver et al., J. Am. Acad. Adolesc. Psychiatry, Vol 35, December, 1996) and botulinum toxin treatment (Esper et al., supra). While each of these treatments has offered clinically significant relief to individual patients, none has replaced neuroleptics as the treatment of choice. Clearly, there is a need for additional treatments for tics and TS that do not carry the side effects and long term risks of neuroleptics.
It has been suggested, on theoretical grounds, that future therapies for Tourette's syndrome might include glutamate antagonists, although a recent article proposing their use makes no mention of any specific drugs that might fulfill this role (Chappell et al., Neurol. Clin. May, 15(2):429-450, 1997). 4).
Magnesium and Movement Disorders
There is considerable evidence for abnormalities of magnesium status in patients with severe mental illness (see for example, Athanassenas et al., J. Clin. Psychopharmacol. August, 3:212-6, 1983; Alexander et al., Br. J. Psychiatry, August, 133:143-9, 1978; Kirov et al., Neuropsychobiology, 30(2-3):73-78, 1994; Wang et al, 1997; Yassa et al., Int. Pharmacopsychiatry, 14(1):57-64, 1979). Alexander et al. (supra, 1978) found that those schizophrenic patients developing extrapyramidal side effects from neuroleptics had, on average, lower magnesium levels than those not having such side effects. Neuromuscular excitability and anxiety are common acute manifestations of magnesium depletion. And, there are theoretical reasons to speculate that magnesium deficiency may contribute to a wide range of neurodegenerative disorders (Durlach et al. 1997, supra). However there has been no suggestion that magnesium deficiency is a cause of tardive dyskinesia, other tardive movement disorders, blepharospasm, or other focal dystonias, or that magnesium supplementation could be used to successfully treat or prevent movement disorders, in the absence of overt magnesium deficiency manifested by tetany.
Although the present day pharmacopeia offers a variety of agents to treat the movement disorders described above, none of these agents can prevent or cure these conditions. Furthermore, the most effective systemic drug treatments often are associated with intolerable side effects. Injections of botulinum toxin can be uncomfortable, must be repeated frequently, and often lose their efficacy over time. In addition, when used to treat dystonia of an upper extremity, they may weaken muscles needed for optimal function of the hands. There remains a clear cut need for new systemic treatments for TD, other tardive movement disorders, blepharospasm, and other focal dystonias, that have greater efficacy and fewer side effects than those currently available.